In a bioterror attack, as in a natural outbreak of an infectious disease, cases can appear very quickly and incapacitate the health care system. The CDC has ranked viral hemorrhagic fevers (VHP) among the highest of the potential bioterror threats, in part because of their high case-fatality ratio, their relatively high infectiousness, and the general lack of effective or specific therapies. Because VHP are almost all rare, at least in the West, there has been little impetus to develop and license new therapies or vaccines, so the health care system is virtually inelastic in its ability to accommodate a marked increase in cases such as might occur through a bioterror attack. The very rarity of VHP makes it extremely unlikely that private industry will have sufficient motivation to develop and-VHP treatments for the sake of profit. We also see a critical need for a generic strategy to rapidly develop specific antivirals for known agents, a technology that will serve a dual purpose. Our hypothesis is that peptide and/or single chain antibody inhibitors can be identified that are capable of inhibiting the interaction between SNV and its cell surface receptor, avb3 integrin. These protein-based inhibitors can have in vivo activity and can be readily converted to non-peptide organics in order to increase potency and allow oral availability. Our objective is to have several highly promising, second generation or higher peptides by the onset of 2005, and to have a highly efficient pipeline of 5-10 interestingly effective inhibitors that have in vivo activity and are converted to non-peptide organic compounds by the end of the funding period. This project represents an extension of our R21 AI53334. The R21 award supplied 2 years of funding that enabled us to develop lead compounds that inhibit Sin Nombre virus infection in vitro. We chose phage display technology as our initial platform, since it puts immense drug selection power in the hands of groups with modest resources, such as academic investigators. We have also recently developed our animal models so that drugs may be tested in vivo. As a model VHP, we chose Sin Nombre (SN) hantavirus, a member of the NIAID Group A list of candidate organisms of bioterror, a virus that causes a VHP with high mortality that is indigenous to the United States and for which current treatments are unsatisfactory. Our objective will be accomplished through the following aims: 1. We will characterize and optimize peptides for their ability to neutralize SNV infection in tissue culture; 2. We will use the deer mouse animal infection model to evaluate the efficacy of peptides developed in Aim 3; and 3. We will identify non-peptide organics on the basis of the structural and functional characteristics of peptide inhibitors developed in Aims 1 and 2. We have assembled an interdisciplinary, highly motivated team of investigators with a diverse array of specialized skills to address a problem, the development of antivirals against a model agent of viral hemorrhagic fever. Our investigators have a history of successes together and have access to very modern technological tools both at the level of computation and virology. In the interest of furthering the national security, we are willing to apply these tools to address the etiologic agents of diseases that could attract the attention of bioweaponeers, but that are too uncommon to interest the private sector.